Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression. TNBC cells respond poorly to targeted chemotherapies currently in use and the mortality rate of TNBC remains high. Therefore, it is necessary to identify new chemotherapeutic agents for TNBC. In this study, the anti-cancer effects of 7-α-hydroxyfrullanolide (7HF), derived from Grangea maderaspatana, on MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells were assessed using MTT assay. The mode of action of 7HF in TNBC cells treated with 6, 12 and 24 µM of 7HF was determined by flow cytometry and propidium iodide (PI) staining for cell cycle analysis and annexin V/fluorescein isothiocyanate + PI staining for detecting apoptosis. The molecular mechanism of action of 7HF in TNBC cells was investigated by evaluating protein expression using proteomic techniques and western blotting. Subsequently, 7HF exhibited the strongest anti-TNBC activity toward MDA-MB-468 cells and a concomitantly weak toxicity toward normal breast cells. The molecular mechanism of action of low-dose 7HF in TNBC cells primarily involved G2/M-phase arrest through upregulation of the expression of Bub3, cyclin B1, phosphorylated Cdk1 (Tyr 15) and p53-independent p21. Contrastingly, the upregulation of PP2A-A subunit expression may have modulated the suppression of various cell survival proteins such as p-Akt (Ser 473), FoxO3a and β-catenin. The concurrent apoptotic effect of 7HF on the treated cells was mediated via both intrinsic and extrinsic modes through the upregulation of Bax and active cleaved caspase-7–9 expression and downregulation of Bcl-2 and full-length caspase-7–9 expression. Notably, the proteomic approach revealed the upregulation of the expression of pivotal protein clusters associated with G1/S-phase arrest, G2/M-phase transition and apoptosis. Thus, 7HF exhibits promising anti-TNBC activity and at a low dose, it modulates signal transduction associated with G2/M-phase arrest and apoptosis.

Breast cancer is the leading cause of female mortality worldwide. Although there are several modern treatments for breast cancer, there is a high rate of recurrence for the majority of treatments; therefore, the search for effective anticancer agents continues. The present study aimed to investigate the anti-breast cancer potential of frullanolide, a compound which is isolated and purified from the Grangea maderaspatana plant, for selected human breast cancer cell lines (MCF-7, MDA-MB-468 and MDA-MB-231). The MTT assay was used to assess cytotoxic activity in breast cancer cell lines of treatment with frullanolide at 1.25, 2.5, 5.0, 10.0 and 20.0 µg/ml. Additionally, the apoptotic induction ability of frullanolide at various concentrations [0.5x, 1x and 2x half maximal inhibitory concentration (IC 50)] was investigated by flow cytometry and western blot analysis. Frullanolide exhibited strong anti-breast cancer activity against MDA-MB-468 (IC 50 , 8.04±2.69 µg/ml) and weak cytotoxicity against the MCF-7 (IC 50 , 10.74±0.86 µg/ml) and MDA-MB-231 (IC 50 , 12.36±0.31 µg/ml) cell lines. The IC 50 of frullanolide was high in the human normal epithelial breast cell line (MCF-12A) and mouse fibroblast cell line (L-929). Density plot diagrams revealed that frullanolide induced apoptosis in MCF-7, MDA-MB-468 and MDA-MB-231 cells. Notably, a plausible anticancer mechanism was elucidated via cellular apoptosis by p53-independence in the treated MCF-7 cell line and p53-dependence in the treated MDA-MB-468 and MDA-MB-231 cell lines. In conclusion, the present study demonstrated that frullanolide may exert anticancer activity on breast cancer cell lines by inducing apoptosis. Frullanolide offers a possible novel approach to breast cancer therapy.

Background The increasing prevalence of broad-spectrum ampicillin-resistant and third-generation cephalosporin-resistant Enterobacteriaceae, particularly Escherichia coli and Klebsiella pneumoniae, has become a global concern, with its clinical impacts on both human and veterinary medicine. This study examined the prevalence, antimicrobial susceptibility, and molecular genetic features of extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae isolates from 10 types of raw vegetables. Methods In total, 305 samples were collected from 9 markets in Nakhon Si Thammarat, Thailand, in 2020. Results ESBL-producing E. coli and K. pneumoniae isolates were found in 14 of the 305 samples obtained from 7 out of 10 types of vegetables (4.6% of the total). Further, 14 ESBL-producing E. coli (n = 5/14) and K. pneumoniae isolates (n = 9/14) (1.6% and 3.0%, respectively) were highly sensitive to β-lactam/carbapenem antibiotics (imipenem, 100%). ESBL-producing E. coli (n = 4) and K. pneumoniae isolates (n = 8) were also sensitive to non-β-lactam aminoglycosides (amikacin, 80.00% and 88.89%, respectively). ESBL producers were most resistant to β-lactam antibiotics, including ampicillin (85.71%) and the cephalosporins cefotaxime and ceftazidime (64.29%). The most frequently detected gene in ESBL-producing E. coli and K. pneumoniae was blaSHV. However, two ESBL-producing E. coli isolates also carried three other ESBL-encoding variants, blaTEM, blaCTX-M1, blaGES and blaTEM, blaSHV, blaCTX-M9, which may be due to their association with food chains and humans. Discussion Indeed, our results suggest that raw vegetables are an important source of ESBL-resistant E. coli and K. pneumoniae, which are potentially transmittable to humans via raw vegetable intake.

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